Structure of Human Argonaute2: A Programmable Ribonuclease
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RNA degradation is an important process in all organisms with functions
including cellular clean-up of unwanted RNA, defense against RNA viruses, and a
variety of other cellular strategies involving RNA modifications. RNA
degradation is mediated by ribonucleases (RNases), which are for the most part
relatively non-specific. However, Argonaute proteins are a class of RNases that
degrade target RNAs in a sequence-specific manner. Argonaute proteins acquire
their specificity by binding small RNA molecules, called guide RNAs, which are
then used to locate target RNAs with a complementary nucleotide sequence.
Subsequently, Argonaute either hydrolyzes the target RNA or it recruits
additional molecules known as silencing factors that accelerate the decay of
the RNA target. By choosing an appropriate guide RNA, Argonaute proteins can be
programmed to target any desired RNA sequence and, hence, are of great interest
for potential therapeutic interventions.
Nicole Schirle and Ian MacRae, two researchers from The Scripps Research
Institute, have now shed light on the mechanism of Argonaute proteins. Using
SSRL’s Beam Line 11-1, the scientists determined the crystal structure of
human Argonaute2 (Ago2, 2.3 Å resolution), which was reported in the
journal Science. The structure revealed the binding of the guide RNA
in a hydrophilic channel between two protein lobes, leaving the base edges
solvent exposed and amenable to specific base-pairing with target RNA.
Moreover, the researchers found nucleotides 2–7 of the guide to be in a
helical conformation – a pre-organization that reduces the entropy of
target-RNA binding and enables Argonaute to locate and bind target RNA ten
times faster than complementary RNAs of similar length. Furthermore, the
researchers modeled the interaction of Argonaute with silencing factors such as
TNRC6, a protein with a tryptophan-rich N-terminal region. Based on the
structure of Ago2 in complex with L-tryptophan, the researchers proposed a
novel Argonaute-binding mode, in which two tryptophans are bound in tandem.
Argonaute proteins play an important role in the biological process of RNA
interference (RNAi), i.e. the knockdown of target genes through degradation of
the corresponding messenger RNA (mRNA). RNAi-based therapeutics may provide new
treatments for human diseases, particularly in cases where conventional drugs
cannot be applied. Therefore, a detailed understanding of Ago2 interactions
with target RNA may benefit the design of novel RNAi therapeutics.
Primary Citation
N. T. Schirle and I. J. MacRae, "The Crystal Structure of Human Argonaute2", Science 336, 1037 (2012); doi: 10.1126/science.1221551.
Related Links
- Science Highlight – HTML / PDF
- SSRL Science Highlights Archive
- SSRL Beam Lines
Contacts
Nicole T. Schirle, The Scripps Research InstituteIan J. MacRae, The Scripps Research Institute
